Subneutralizing levels of dengue virus (DENV)-specific antibodies (Abs) can enhance DENV infection in vitro via a phenomenon known as Ab-dependent enhancement of infection (ADE) and are implicated in the immunopathology of secondary DENV infections. Understanding the mechanisms that regulate the balance between Ab-mediated pathology versus protection is crucial for developing a safe dengue vaccine. The overall goal of this project is to advance our understanding of how Abs can play a role in DENV pathogenesis. We have recently generated a model of Ab-induced dengue disease in IFN-&#945;/&#946;and -&#947;receptor-deficient mice, allowing us to investigate the cellular and molecular basis of ADE-induced dengue disease. Using this mouse model, we have already demonstrated that Abs promote massive infection of liver sinusoidal endothelial cells (LSECs), followed by TNF-mediated death of the infected animals. In this project, we will optimize a model of Ab-induced dengue disease in mice lacking IFN-&#945;/&#946;receptor alone and use this model to examine how infection of LSECs leads to TNF production (Specific Aim 1), define the properties of Abs and role of Fc-&#947; receptors in mediating Ab-induced dengue disease (Specific Aim 2), and to determine whether T cells contribute to DENV pathogenesis (Specific Aim 3). The proposed research will establish an essential foundation towards understanding the mechanisms by which Abs can contribute to viral diseases, as little is known about ADE of viral infections in vivo.